The present invention relates generally to treatments of neurodegenerative disorders, and more particularly to treatments of Parkinson's disease.
Neurodegenerative disorders are a group of central nervous system disorders characterized by the gradual and progressive loss of neural tissues or nerve cells. Neurodegenerative disorders manifest themselves at various levels resulting in very diverse symptoms, including partial or complete loss of motor functions, partial or complete loss of memory, partial or complete loss of speech, partial or complete loss of cognitive skills and behavioral changes, etc. Neurodegenerative disorders include Alzheimer's disease (ALZ), Parkinson's Disease (PD), Huntington's Disease and Amyotrophic lateral sclerosis (ALS).
Of the neurodegenerative disorders, Parkinson's disease (also known as Parkinson's or PD) affects millions of individuals every year. Although its cause remains unknown, PD is associated with the loss or reduction of dopamine-producing neurons. Dopamine is a hormone produced by the brain. It is a chemical messenger that affects the brain processes that control, among other things, movement, emotional response, and the capacity to feel pleasure and pain. The loss or reduction of dopamine is believed to directly or indirectly cause the symptoms of PD.
PD is characterized by muscle rigidity, tremor, postural abnormalities, gait abnormalities, a slowing of physical movement (bradykinesia) or a loss of physical movement (akinesia) in extreme cases. Other symptoms may include gradual loss of cognitive abilities, depression, emotional changes, behavioral changes, loss of speech, and difficulty in swallowing, chewing and sleep disruptions.
Currently there is no cure for PD or other neurodegenerative disorders, since no known treatment can stop or reverse the breakdown of nerve cells. Treatments for PD aim primarily to alleviate PD-induced symptoms. Treatments for treating PD-induced symptoms can be grouped in two main categories: surgical procedures and pharmacological therapies (Table 1).
In severely affected PD patients, as shown in Table 1, surgical procedures, including ablation, deep brain stimulation, pallidotomy and cerebral transplantation, are considered. In ablation, a defined area of the brain deemed affected by Parkinson's is destroyed. In deep brain stimulation, the targeted area is inactivated by implanted electrodes. Pallidotomy is a delicate surgical procedure wherein a fine probe measures abnormal electrical activity of a precise region of the brain, and another probe delivers small electric shocks. The patient, who is awake during the surgery, describes the effects of the electric shocks to pinpoint the area for treatment. The surgeon then burns a tiny hole in the affected cells. Cerebral transplantation implants dopamine-producing cells into the brain. Surgical procedures are invasive, carry inherent risks of infection, stroke or internal bleeding, and have adverse side effects. Furthermore, their effectiveness is uncertain.
For most PD patients, treatment centers on the administration of medications to relieve symptoms. Table 1 lists some common classes of therapies or medications used to treat PD patients. Every patient responds differently to a medication or dosage level, thus treatment needs to be tailored to each individual, taking into consideration various factors such as severity of symptoms, age, and other concurrent medical issues. All medications cause adverse side effects, as further discussed below.
TABLE 1SURGICAL TREATMENTSPHARMACOLOGICAL TREATMENTSAblationCarbidopa/Levodopa therapyDeep brain stimulationDopamine AgonistsPallidotomyAnticholinergicsCerebral TransplantationMAO-B InhibitorsCOMT InhibitorsOthers
Of the currently available pharmacological treatments, levodopa is considered the most effective medication for treating PD symptoms. Levodopa is converted into dopamine by an enzyme in the brain. Levodopa does not slow the disease process, but it improves muscle movement and delays severe disability. However, levodopa can cause many side effects, including nausea, vomiting, headache, dizziness, fainting, weakness, decreased blood pressure. In elderly patients, levodopa can cause depression, confusion and visual hallucination. Furthermore, levodopa can become ineffective over time. Increased dosing and prolonged use of levodopa cause additional side effects, such as dyskinesias (spontaneous, involuntary movements) and “on-off” periods when the medication suddenly and unpredictably starts or stops working.
Levodopa is generally used in combination with other medications. Among these, carbidopa prolongs the effect of levodopa by blocking the breakdown of levodopa in the liver, thus increasing the amount of levodopa that reaches the brain. Therefore, a smaller dose of levodopa is needed to treat symptoms. In addition, carbidopa reduces some of the nausea and vomiting associated with levodopa treatment. However, adverse side effects caused by levodopa treatment as discussed above are still prevalent in carbidopa/levodopa therapy.
Referring again to Table 1, another class of pharmacological treatments for PD includes dopamine agonists, which mimic dopamine's function in the brain. Dopamine agonists can be used alone, but they are generally less effective in controlling symptoms. Therefore, they are used primarily as adjuncts to levodopa/carbidopa therapy. Side effects of dopamine agonists include nausea, sleepiness, dizziness, and headache.
Anticholinergics, another class of medications to treat PD, do not act directly on the dopaminergic system but they decrease the activity of acetylcholine, another chemical messenger that controls movement, to balance the diminished dopamine activity. They are also used as adjuncts to levodopa. Adverse effects of anticholinergics include blurred vision, dry mouth and urinary retention. In older patients, they can cause confusion and hallucination.
MAO-B inhibitors, which belong to another class of medications for alleviating PD-induced symptoms, are also used in combination with levodopa. MAO-B inhibitors boost the effects of levodopa by preventing the breakdown of dopamine, thus increasing the amount of available dopamine in the brain. Side effects of MAO-B inhibitors include nausea, dizziness, abdominal pain, confusion, hallucinations and dry mouth.
COMT inhibitors, another class of PD medications, generally must be taken with levodopa. COMT inhibitors prolong symptom relief by blocking the action of an enzyme which breaks down levodopa, allowing a larger amount of levodopa to reach the brain, which raises the dopamine level. Side effects of COMT inhibitors include vivid dreams, visual hallucination, nausea, sleep disturbances, daytime drowsiness, headache and dyskinesia.
It is common for PD patients to take a variety of these medications, all at different doses and at different times of day in order to manage the symptoms of the disease. Variable dosing during a particular day or between days may result in decreased effectiveness of treatment or symptoms management during a day or between days. In addition to the described side effects, prolonged use and increased dosing of the medications render them ineffective over time, or result in “on-off” periods when the medications suddenly and unpredictably start or stop working. Therefore, drug dosage and medication regimens generally are constantly monitored and adjusted to manage the PD symptoms as well as the side effects.